Novel A2A Adenosine Agonists in Vascular Protection

描述（由申请人提供）：这是一项开发新型药物洗脱支架以防止再狭窄的II期SBIR提案。这是Adenosine Therapeutics， LLC, Setagon, Inc.和弗吉尼亚大学之间的三方合作。本文描述的工作将在Adenosine Therapeutics（化合物合成和药代动力学）和弗吉尼亚大学（猪支架研究）完成。纳米多孔支架涂层将由seagon公司提供，以优化两种药物的输送。该提案的目的是证明，将两种协同抗炎化合物ATL146e （A2A腺苷受体激动剂）和罗利普兰（IV型磷酸二酯酶（PDE）抑制剂）联合使用，装入专有的纳米多孔支架涂层中，比目前最先进的聚合物支架涂层更有效地抑制猪支架再狭窄。如果这些实验是成功的，我们的计划是开发ATL146e/罗利普兰支架作为一个新产品。ATL146e和罗利普兰都被批准用于男性，Adenosine Therapeutics已经为这些化合物的联合使用颁发了专利，以防止再狭窄。目的1研究体外支架中ATL146e和罗利普兰的洗脱动力学。在这个目的中，我们还将利用从猪血液中提取的化合物的液相色谱/质谱分析，确定ATL146e和罗利普兰在猪体内的最终处置半衰期。根据这些数据，我们将在支架上加载足以使游离血浓度仅为1 ng/kg的化合物，这不太可能产生副作用。目的2研究装载了ATL146e+/-罗利普兰的猪支架的再狭窄。结果将与含有西罗莫司作为金标准的市售支架进行比较。由于ATL146e和罗利普兰都已被批准用于人体，我们预计，如果这项研究的结果表明ATL146e +/-罗利普兰比西罗莫司更有效，将有可能启动II期临床试验来测试ATL146e/罗利普兰支架在人体中的应用。

DESCRIPTION (provided by applicant): This is a phase II SBIR proposal to develop a new drug eluting stent to prevent restenosis. It is a 3-way collaboration between Adenosine Therapeutics, LLC, Setagon, Inc., and the University of Virginia. The work described here will be done at Adenosine Therapeutics (compound synthesis and pharmacokinetics) and the University of Virginia (Stent studies in pigs). The nanoporous stent coating will be refined for optimal delivery of two drugs and provided by Setagon, Inc. The goal of this proposal is to demonstrate that the combined used of two synergistic anti-inflammatory compounds, ATL146e, an agonist of A2A adenosine receptors, and rolipram, a type IV phosphodiesterase (PDE) inhibitor, loaded into a proprietary nanoporous stent coating, inhibits stent restenosis in pigs more effectively than current state-of-the-art polymeric stent coatings. If these experiments are successful our plan is to develop the ATL146e/rolipram stent as a new product. ATL146e and rolipram are both approved for use in man and Adenosine Therapeutics has issued patents for the combined use of these compounds to prevent restenosis. Aim 1 proposes to investigate the elution kinetics of ATL146e and rolipram from stents into blood in vitro. In this aim we also will determine the terminal disposition half-life of ATL146e and rolipram in pigs using liquid chromatography/ mass spectroscopy of compounds extracted from pig blood after intravenous administration. Based on these data we will load stents with compounds sufficient to achieve free blood concentrations of only 1 ng/kg, that are unlikely to produce side effects. Aim 2 proposes to examine restenosis in pigs of stents loaded with ATL146e+/- rolipram. The results will be compared to commercially available stents containing sirolimus as a gold standard. Since ATL146e and rolipram have both been approved for human use, we anticipate that if the results of this study show that ATL146e +/- rolipram is more effective that sirolimus, it will be possible to initiate phase II clinical trials to test ATL146e/rolipram stents in man.